Memantine increases cardiovascular but not behavioral effects of cocaine in methadone-maintained humans

Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 02/2006; 83(1):47-55. DOI: 10.1016/j.pbb.2005.12.003
Source: PubMed


Previous work has suggested that maintenance on the noncompetitive N-methyl-d-aspartate (NMDA) antagonist, memantine, increased the subjective effects of smoked cocaine in experienced cocaine users. To determine whether this phenomenon occurs in opioid-dependent individuals, eight (seven male, one female) methadone-maintained cocaine smokers participated in a 47-day inpatient and outpatient study to assess the effects of memantine on smoked cocaine self-administration, subjective effects, and cardiovascular responses. The participants were maintained on memantine (0 mg and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition during inpatient phases, participants smoked a sample dose of cocaine base (0, 12, 25, and 50 mg) once, and were subsequently given five choice opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher (US 5.00 dollars). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose were varied systematically. Memantine maintenance did not alter the subjective or reinforcing effects of cocaine. Several cardiovascular responses, however, including peak and initial diastolic pressures following cocaine, were significantly greater during memantine maintenance, although these elevations were not clinically significant. Taken together, these findings corroborate earlier data suggesting that this dose of memantine will not be helpful in the pharmacotherapy of cocaine abuse.

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    • "The mechanism for this activity is not well understood. Collins et al.25 revealed that left ventricular peak and end-diastolic pressures following cocaine use were greater in individuals treated with memantine, although these elevations were not clinically significant. In another study examining memantine’s effect on cardiovascular parameters, Herrero et al.26 found that memantine did not significantly affect blood pressure. "
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    ABSTRACT: Memantine is an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist used to treat Alzheimer's disease. Previous studies have suggested that receptor blockers act as neuroprotective agents; however, no study has specifically investigated the impact that these drugs have on the heart. We sought to evaluate the effects of memantine on nuclear size reduction in cardiac cells exposed to cold stress. We used male EPM-Wistar rats (n=40) divided into 4 groups: 1) Matched control (CON); 2) Memantine-treated rats (MEM); 3) Rats undergoing induced hypothermia (IH) and 4) Rats undergoing induced hypothermia that were also treated with memantine (IHM). Animals in the MEM and IHM groups were treated by oral gavage administration of 20 mg/kg/day memantine over an eight-day period. Animals in the IH and IHM groups were submitted to 4 hours of hypothermia in a controlled environment with a temperature of -8 degrees C on the last day of the study. The MEM group had the largest cardiomyocyte nuclear size (151 +/- 3.5 microm(3) vs. CON: 142 +/- 2.3 microm(3); p<0.05), while the IH group had the smallest mean value of nuclear size. The nuclear size of the IHM group was preserved (125 +/- 2.9 microm(3)) compared to the IH group (108 +/- 1.7 microm(3); p<0.05). Memantine prevented the nuclear size reduction of cardiomyocytes in rats exposed to cold stress.
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    ABSTRACT: The present study evaluates the effect of memantine, a non-competitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist and CNQX, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist on the rewarding effects of cocaine in mice, using the conditioned place preference (CPP) paradigm. Cocaine-induced CPP was studied pairing this drug with different memantine or CNQX doses during either the acquisition or the expression phase of the procedure. Once CPP was established, and the preference extinguished, reinstatement was induced by a priming dose of cocaine. Both antagonists, which in themselves do not present motivational actions on the preference shown by the animals, abolished the acquisition and expression of the cocaine-induced CPP. Neither of the antagonists precipitated reinstatement of the preference induced by cocaine but memantine blocked the cocaine-primed reinstatement. Our results suggest that cocaine-induced CPP and reinstatement is largely dependent on glutamate neurotransmission, and confer a putative role for memantine among the tools useful for cocaine management and treatment.
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    ABSTRACT: This study examined the acute effects of pretreatment with high-dose memantine, an N-methyl-D-aspartate antagonist, on the effects of cocaine in humans. Six African American men completed this laboratory study, in which, following pretreatment with memantine (0 or 60 mg), they had 5 opportunities to smoke cocaine base (0, 12, 25, or 50 mg) or receive an alternative reinforcer ($5.00 merchandise voucher). Cocaine alone produced the well-documented dose-dependent increases in cardiovascular activity and ratings of positive mood. Maximal systolic blood pressure was elevated during memantine pretreatment days. Peak ratings of "I feel stimulated" and "I feel anxious" were also higher with memantine pretreatment. However, memantine pretreatment did not alter the choice to self-administer cocaine. These data suggest that memantine pretreatment may not be helpful in the treatment of cocaine dependence.
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